Delayed globin synthesis leads to excess heme and the macrocytic anemia of Diamond Blackfan anemia and del(5q) myelodysplastic syndrome

Science Translational Medicine

Volumn 8, Issue 338, 2016, Pages

  Yang, Zhantao ^a   Keel, Siobán B ^a   Shimamura, Akiko ^b,c,e   Liu, Li ^a   Gerds, Aaron T ^b,f   Li, Henry Y ^d   Wood, Brent L ^a   Scott, Bart L ^b   Abkowitz, Janis L ^a  

^a UNIVERSITY OF WASHINGTON   (United States)

^b USA   (United States)

^c SEATTLE CHILDREN S HOSPITAL   (United States)

^d Polyclinic   (United States)

^e BOSTON CHILDREN S HOSPITAL   (United States)

^f LERNER RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GLOBIN; HEME; HEMOGLOBIN ALPHA CHAIN; HEMOGLOBIN BETA CHAIN; MESSENGER RNA; REACTIVE OXYGEN METABOLITE; SUCCINYLACETONE;

5Q- SYNDROME; ADULT; ARTICLE; BLACKFAN DIAMOND ANEMIA; BONE MARROW CELL; CELL SURVIVAL; CLINICAL ARTICLE; COLONY FORMING UNIT E; CONTROLLED STUDY; ERYTHROBLAST; ERYTHROID CELL; ERYTHROID PRECURSOR CELL; ERYTHROPOIESIS; FEMALE; GLOBIN SYNTHESIS; HEME SYNTHESIS; HUMAN; HUMAN CELL; IN VITRO STUDY; MACROCYTIC ANEMIA; PRIORITY JOURNAL; PROERYTHROBLAST; ANEMIA; FLOW CYTOMETRY; METABOLISM; MYELODYSPLASTIC SYNDROME; PHYSIOLOGY;

ADULT; ANEMIA; ANEMIA, DIAMOND-BLACKFAN; ANEMIA, MACROCYTIC; ERYTHROID CELLS; ERYTHROPOIESIS; FEMALE; FLOW CYTOMETRY; GLOBINS; HEME; HUMANS; MYELODYSPLASTIC SYNDROMES; REACTIVE OXYGEN SPECIES;

EID: 84969221188     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aaf3006     Document Type: Article

References (48)

1. M. Landowski, M.-F. ODonohue, C. Buros, R. Ghazvinian, N. Montel-Lehry, A. Vlachos, C. A. Sieff, P. E. Newburger, E. Niewiadomska, M.Matysiak, B. Glader, E. Atsidaftos, J. M. Lipton, A. H. Beggs, P.-E. Gleizes, H. T. Gazda, Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond-Blackfan anemia. Hum. Genet. 132, 1265-1274 (2013).
2. R. Horos, M. von Lindern, Molecular mechanisms of pathology and treatment in Diamond Blackfan Anaemia. Br. J. Haematol. 159, 514-527 (2012).
3. S. Fumagalli, A. Di Cara, A. Neb-Gulati, F. Natt, S. Schwemberger, J. Hall, G. F. Babcock, R. Bernardi, P. P. Pandolfi, G. Thomas, Absence of nucleolar disruption after impairment of 40S ribosome biogenesis reveals an rpL11-Translation-dependent mechanism of p53 induction. Nat. Cell Biol. 11, 501-508 (2009).
4. S. Dutt, A. Narla, K. Lin, A. Mullally, N. Abayasekara, C. Megerdichian, F. H. Wilson, T. Currie, A. Khanna-Gupta, N. Berliner, J. L. Kutok, B. L. Ebert, Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells. Blood 117, 2567-2576 (2011).
5. S. R. Ellis, Nucleolar stress in Diamond Blackfan anemia pathophysiology. Biochim. Biophys. Acta 1842, 765-768 (2014).
6. P. Jaako, S. Debnath, K. Olsson, Y. Zhang, J. Flygare, M. S. Lindström, D. Bryder, S. Karlsson, Disruption of the 5S RNP-Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond-Blackfan anemia. Leukemia 29, 2221-2229 (2015).
7. R. Horos, H. Ijspeert, D. Pospisilova, R. Sendtner, C. Andrieu-Soler, E. Taskesen, A. Nieradka, R. Cmejla, M. Sendtner, I. P. Touw, M. von Lindern, Ribosomal deficiencies in Diamond-Blackfan anemia impair translation of transcripts essential for differentiation of murine and human erythroblasts. Blood 119, 262-272 (2012).
8. M. A. Rey, S. P. Duffy, J. K. Brown, J. A. Kennedy, J. E. Dick, Y. Dror, C. S. Tailor, Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis. Haematologica 93, 1617-1626 (2008).
9. L. S. Ludwig, H. T. Gazda, J. C. Eng, S.W. Eichhorn, P. Thiru, R. Ghazvinian, T. I. George, J. R. Gotlib, A. H. Beggs, C. A. Sieff, H. F. Lodish, E. S. Lander, V. G. Sankaran, Altered translation of GATA1 in Diamond-Blackfan anemia. Nat. Med. 20, 748-753 (2014).
10. B. L. Ebert, J. Pretz, J. Bosco, C. Y. Chang, P. Tamayo, N. Galili, A. Raza, D. E. Root, E. Attar, S. R. Ellis, T. R. Golub, Identification of RPS14 as a 5q-syndrome gene by RNA interference screen. Nature 451, 335-339 (2008).
11. J. L. Barlow, L. F. Drynan, D. R. Hewett, L. R. Holmes, S. Lorenzo-Abalde, A. L. Lane, H. E. Jolin, R. Pannell, A. J. Middleton, S. H. Wong, A. J. Warren, J. S. Wainscoat, J. Boultwood, A. N. J. McKenzie, A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q-syndrome. Nat. Med. 16, 59-66 (2010).
12. J. Hu, J. Liu, F. Xue, G. Halverson, M. Reid, A. Guo, L. Chen, A. Raza, N. Galili, J. Jaffray, J. Lane, J. A. Chasis, N. Taylor, N. Mohandas, X. An, Isolation and functional characterization of human erythroblasts at distinct stages: Implications for understanding of normal and disordered erythropoiesis in vivo. Blood 121, 3246-3253 (2013).
13. J. Li, J. Hale, P. Bhagia, F. Xue, L. Chen, J. Jaffray, H. Yan, J. Lane, P. G. Gallagher, N. Mohandas, J. Liu, X. An, Isolation and transcriptome analyses of human erythroid progenitors: BFU-E and CFU-E. Blood 124, 3636-3645 (2014).
14. M. W. Hentze, M. U. Muckenthaler, B. Galy, C. Camaschella, Two to tango: Regulation of mammalian iron metabolism. Cell 142, 24-38 (2010).
15. H. Suzuki, S. Tashiro, S. Hira, J. Sun, C. Yamazaki, Y. Zenke, M. Ikeda-Saito, M. Yoshida, K. Igarashi, Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1. EMBO J. 23, 2544-2553 (2004).
16. T. Tahara, J. Sun, K. Nakanishi, M. Yamamoto, H. Mori, T. Saito, H. Fujita, K. Igarashi, S. Taketani, Heme positively regulates the expression of b-globin at the locus control region via the transcriptional factor Bach1 in erythroid cells. J. Biol. Chem. 279, 5480-5487 (2004).
17. A.-P. Han, C. Yu, L. Lu, Y. Fujiwara, C. Browne, G. Chin, M. Fleming, P. Leboulch, S. H. Orkin, J.-J. Chen, Heme-regulated eIF2a kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency. EMBO J. 20, 6909-6918 (2001).
18. R. S. Ajioka, J. D. Phillips, J. P. Kushner, Biosynthesis of heme in mammals. Biochim. Biophys. Acta 1763, 723-736 (2006).
19. H. A. Dailey, P. N. Meissner, Erythroid heme biosynthesis and its disorders. Cold Spring Harb. Perspect. Med. 3, a011676 (2013).
20. S. B. Keel, R. T. Doty, Z. Yang, J. G. Quigley, J. Chen, S. Knoblaugh, P. D. Kingsley, I. De Domenico, M. B. Vaughn, J. Kaplan, J. Palis, J. L. Abkowitz, A heme export protein is required for red blood cell differentiation and iron homeostasis. Science 319, 825-828 (2008).
21. J. G. Quigley, Z. Yang, M. T. Worthington, J. D. Phillips, K. M. Sabo, D. E. Sabath, C. L. Berg, S. Sassa, B. L. Wood, J. L. Abkowitz, Identification of a human heme exporter that is essential for erythropoiesis. Cell 118, 757-766 (2004).
22. N. G. Testa, D. Onions, O. Jarrett, F. Frassoni, J. F. Eliason, Haemopoietic colony formation (BFU-E, GM-CFC) during the development of pure red cell hypoplasia induced in the cat by feline leukaemia virus. Leuk. Res. 7, 103-116 (1983).
23. J. L. Abkowitz, Retrovirus-induced feline pure red cell aplasia: Pathogenesis and response to suramin. Blood 77, 1442-1451 (1991).
24. R. T. Doty, S. R. Phelps, C. Shadle, M. Sanchez-Bonilla, S. B. Keel, J. L. Abkowitz, Coordinate expression of heme and globin is essential for effective erythropoiesis. J. Clin. Invest. 125, 4681-4691 (2015).
25. W. S. Yang, R. SriRamaratnam, M. E. Welsch, K. Shimada, R. Skouta, V. S. Viswanathan, J. H. Cheah, P. A. Clemons, A. F. Shamji, C. B. Clish, L. M. Brown, A. W. Girotti, V. W. Cornish, S. L. Schreiber, B. R. Stockwell, Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317-331 (2014).
26. S. J. Dixon, K. M. Lemberg, M. R. Lamprecht, R. Skouta, E. M. Zaitsev, C. E. Gleason, D. N. Patel, A. J. Bauer, A. M. Cantley, W. S. Yang, B. Morrison III, B. R. Stockwell, Ferroptosis: An irondependent form of nonapoptotic cell death. Cell 149, 1060-1072 (2012).
27. J. P. Friedmann Angeli, M. Schneider, B. Proneth, Y. Y. Tyurina, V. A. Tyurin, V. J. Hammond, N. Herbach, M. Aichler, A. Walch, E. Eggenhofer, D. Basavarajappa, O. Radmark, S. Kobayashi, T. Seibt, H. Beck, F. Neff, I. Esposito, R. Wanke, H. Förster, O. Yefremova, M. Heinrichmeyer, G. W. Bornkamm, E. K. Geissler, S. B. Thomas, B. R. Stockwell, V. B. ODonnell, V. E. Kagan, J. A. Schick, M. Conrad, Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell. Biol. 16, 1180-1191 (2014).
28. M. C. Giarratana, H. Rouard, A. Dumont, L. Kiger, I. Safeukui, P.-Y. Le Pennec, S. Francois, G. Trugnan, T. Peyrard, T. Marie, S. Jolly, N. Hebert, C. Mazurier, N. Mario, L. Harmand, H. Lapillonne, J.-Y. Devaux, L. Douay, Proof of principle for transfusion of in vitro-generated red blood cells. Blood 118, 5071-5079 (2011).
29. P. Ponka, A. Wilczynska, H. M. Schulman, Iron utilization in rabbit reticulocytes. A study using succinylacetone as an inhibitor or heme synthesis. Biochim. Biophys. Acta 720, 96-105 (1982).
30. Z. Yang, J. D. Philips, R. T. Doty, P. Giraudi, J. D. Ostrow, C. Tiribelli, A. Smith, J. L. Abkowitz, Kinetics and specificity of feline leukemia virus subgroup C receptor (FLVCR) export function and its dependence on hemopexin. J. Biol. Chem. 285, 28874-28882 (2010).
31. D. G. Nathan, S. Piomelli, F. H. Gardner, The synthesis of heme and globin in the maturing human erythroid cell. J. Clin. Invest. 40, 940-946 (1961).
32. S. Ghaffari, Oxidative stress in the regulation of normal and neoplastic hematopoiesis. Antioxid. Redox Signal. 10, 1923-1940 (2008).
33. K. Igarashi, M. Watanabe-Matsui, Wearing red for signaling: The heme-bach axis in heme metabolism, oxidative stress response and iron immunology. Tohoku J. Exp. Med. 232, 229-253 (2014).
34. J.-J. Chen, Translational control by heme-regulated eIF2a kinase during erythropoiesis. Curr. Opin. Hematol. 21, 172-178 (2014).
35. L. Jiang, N. Kon, T. Li, S.-J. Wang, T. Su, H. Hibshoosh, R. Baer, W. Gu, Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520, 57-62 (2015).
36. H. J. Warnatz, D. Schmidt, T. Manke, I. Piccini, M. Sultan, T. Borodina, D. Balzereit, W. Wruck, A. Soldatov, M. Vingron, H. Lehrach, M.-L. Yaspo, The BTB and CNC homology 1 (BACH1) target genes are involved in the oxidative stress response and in control of the cell cycle. J. Biol. Chem. 286, 23521-23532 (2011).
37. S. Wei, X. Chen, K. McGraw, L. Zhang, R. Komrokji, J. Clark, G. Caceres, D. Billingsley, L. Sokol, J. Lancet, N. Fortenbery, J. Zhou, E. A. Eksioglu, D. Sallman, H. Wang, P. K. Epling-Burnette, J. Djeu, M. Sekeres, J. P. Maciejewski, A. List, Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion. Oncogene 32, 1110-1120 (2013).
38. A. Narla, S. Dutt, J. R. McAuley, F. Al-Shahrour, S. Hurst, M. McConkey, D. Neuberg, B. L. Ebert, Dexamethasone and lenalidomide have distinct functional effects on erythropoiesis. Blood 118, 2296-2304 (2011).
39. K. A. McGowan, P. J. Mason, Animal models of Diamond Blackfan anemia. Semin. Hematol. 48, 106-116 (2011).
40. S. B. Keel, S. Phelps, K. M. Sabo, M. N. OLeary, C. B. Kirn-Safran, J. L. Abkowitz, Establishing Rps6 hemizygous mice as a model for studying how ribosomal protein haploinsufficiency impairs erythropoiesis. Exp. Hematol. 40, 290-294 (2012).
41. P. Jaako, J. Flygare, K. Olsson, R. Quere, M. Ehinger, A. Henson, S. Ellis, A. Schambach, C. Baum, J. Richter, J. Larsson, D. Bryder, S. Karlsson, Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond-Blackfan anemia. Blood 118, 6087-6096 (2011).
42. L. Morgado-Palacin, G. Varetti, S. Llanos, G. Gómez-López, D. Martinez, M. Serrano, Partial loss of Rpl11 in adult mice recapitulates Diamond-Blackfan Anemia and promotes lymphomagenesis. Cell Rep. 13, 712-722 (2015).
43. K. A. McGowan, W. W. Pang, R. Bhardwaj, M. G. Perez, J. V. Pluvinage, B. E. Glader, R. Malek, S. M. Mendrysa, I. L. Weissman, C. Y. Park, G. S. Barsh, Reduced ribosomal protein gene dosage and p53 activation in low-risk myelodysplastic syndrome. Blood 118, 3622-3633 (2011).
44. A. F. List, M. R. Baer, D. P. Steensma, A. Raza, J. Esposito, N. Martinez-Lopez, C. Paley, J. Feigert, E. Besa, Deferasirox reduces serum ferritin and labile plasma iron in RBC transfusion-dependent patients with myelodysplastic syndrome. J. Clin. Oncol. 30, 2134-2139 (2012).
45. M. Delforge, D. Selleslag, Y. Beguin, A. Triffet, P. Mineur, K. Theunissen, C. Graux, F. Trullemans, D. Boulet, K. Van Eygen, L. Noens, S. Van Steenweghen, J. Lemmens, P. Pierre, R. DHondt, A. Ferrant, D. Deeren, A. Van De Velde, W. Wynendaele, M. André, R. De Bock, A. Efira, D. Breems, A. Deweweire, K. Geldhof, W. Pluymers, A. Harrington, K. MacDonald, I. Abraham, C. Ravoet, Adequate iron chelation therapy for at least six months improves survival in transfusion-dependent patients with lower risk myelodysplastic syndromes. Leuk. Res. 38, 557-563 (2014).
46. J. Hartmann, F. Braulke, U. Sinzig, G. Wulf, J. H. Maas, F. Konietschke, D. Haase, Iron overload impairs proliferation of erythroid progenitors cells (BFU-E) from patients with myelodysplastic syndromes. Leuk. Res. 37, 327-332 (2013).
47. P. R. Sinclair, N. Gorman, J. M. Jacobs, Measurement of heme concentration, in Current Protocols in Toxicology, M. D. Maines, Ed. (Wiley, New York, 2001), chap. 8.3, pp. 8.3.1-8.3.7.
48. J. L. Abkowitz, G. Schaison, F. Boulad, D. L. Brown, G. R. Buchanan, C. A. Johnson, J. C. Murray, K. M. Sabo, Response of Diamond-Blackfan anemia to metoclopramide: Evidence for a role for prolactin in erythropoiesis. Blood 100, 2687-2691 (2002).